Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by resting tremor, rigidity and bradykinesia. These clinical features are thought to arise from reduced dopaminergic input to the striatum, which is caused by the degeneration of dopaminergic neurons in the substantia nigra. The occurrence of PD is largely sporadic, but clinical syndromes resembling sporadic PD have been linked to mutations in at least 5 distinct genes (a-synuclein, parkin, DJ-1, PINK1 and LRRK2). Elucidation of the pathogenic mechanism underlying the selective dopaminergic degeneration in familial PD will likely provide important clues to the pathogenic mechanism responsible for idiopathic PD. Mutations in LRRK2 are the most common genetic cause of late-onset PD, but the normal physiological role of mammalian LRRK2 is unknown. Interestingly, multiple amino acid substitutions (R1441C, R1441G, and R1441H) have been identified on the same R1441 residue in the highly conserved GTPase domain, highlighting the importance of this residue in PD pathogenesis. Our generation and multidisciplinary analysis of LRRK2 knockin (KI) mice suggests that the R1441C mutation impairs dopaminergic neurotransmission and dopamine D2 receptor-mediated functions. In this application, we propose the following two Specific Aims to uncover the normal physiological role of LRRK2 in mice and to investigate the pathogenic mechanism by which LRRK2 mutations cause PD. First, we will determine the normal physiological role of LRRK2 in vivo. Second, we will determine how LRRK2 mutations affect dopaminergic neurotransmission. The central hypothesis guiding our proposal is that pathogenic PD mutations alter the normal functions of the PD gene products and cause dopaminergic dysfunction, which plays central roles in PD pathogenesis, ultimately leading to their degeneration and production of the parkinsonian phenotypes. The completion of the proposed study will uncover the normal physiological role of LRRK2 and provide mechanistic insight into how LRRK2 pathogenic mutations cause PD. Our long-term goal is to understand the pathogenic mechanism underlying dopaminergic dysfunction and degeneration, and to characterize the cellular and molecular pathways responsible for PD pathogenesis. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the most common movement disorder, and mutations in the LRRK2 gene are the most common genetic cause for late-onset PD. In this application, we propose to investigate the mechanisms by which mutations in LRRK2 cause PD and to determine the physiological role of LRRK2 in mice. Completion of our proposed study will provide insights into PD pathogenesis and may identify novel therapeutic targets for development of more effective drugs.